Esters of 4-phenyl-4-tetrahydropyrancarboxylic acid and their salts



United States Patent O ESTERS OF 4-PHENYL-4-TETRAI IYDllOPYRAN- CARBOXYLIC ACID AND THEIR SALTS William W. Jenkins, Morton Grove, Ill., assig'nor, by mesne assignments, to G. D. Searle & (10., Skokie, Ill., a corporation of Delaware N Drawing. Application May 10, 1954, Serial No. 428,846

6 Claims. (Cl. 260-2943) The present invention relates to new drugs with valuable cardio-regulatory properties and, in particular, to certain esters of 4-phenyl-4-tetrahydropyrancarboxylic acid and their non-toxic salts. These esters can be represented by the structural formula wherein Alk is a lower alkylene radical separating the oxygen and nitrogen atoms attached thereto by at least two carbon atoms and NRR is a member of the class consisting of di-n-propylarnino, diisopropylamino, di-(secondary butyl)amino, 2,5-dimethylpyrrolidino and 2,6- lupetidino radicals.

These compounds have a strong quinidine-like action on auricles. As stated in mycopending application Serial No. 282,703, filed April 16, 1952, now abandoned, of which the present application is a continuation-in-part, the hydrochloride of the ,B-diisopropylaminoethyl ester was found to be about 4 times as active as quinidine when tested by the method of G. S. Dawes, described in the British Journal of Pharmacology, vol. 1, page 90, 1946.

This result was quite unexpected since the hydrochloride of the corresponding ,B-diethylaminoethyl ester had proven to be only about 0.4 times as active as quinidine in the same test. Further investigation in this series has shown that certain additional, related esters share the high degree of activity shown by the fl-diisopropylaminoethyl ester. Specifically, it was found that on replacement of the diisopropylamino group by a di-n-propylamino and di-sec.-butylamino group the activity was maintained. However, replacement of the isopropyl group by a higher alkyl group or by a butyl group which is not branched at the 01- carbon atom such as an isobuty-l group leads to a disappearance of the activity. The dialkylamino group can also be replaced by a 2,5-dimethylpyrrolidino or 2,6 lupetidino radical. However, it has been found that related nitrogen-containing heterocycles lacking the branched methyl groups at the 06- carbon atom such as the N-pyrrolidino and N-morpholino derivatives are inactive.

The esters of this invention form salts with a variety of non-toxic, inorganic and strong organic acids including sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic, citric, oxalic, ascorbic and related acids. They also form quaternary ammonium salts with a variety of organic esters of sulfuric, hydrohalic and aromatic sulfonic acids which provide anions which are non-toxic in therapeutic dosages. Among such esters are methyl chloride and bromide; ethyl chloride, propyl chloride, butyl chloride,

isobutyl chloride, benzyl bromide, phenethyl bromide, di-

2,774,765 Patented Dec. 18, 1956 2 methyl sulfate, diethyl sulfate, methyl benzenesulfonate, ethyl toluenesulfonate, ethylene chlorohydrin, propylene chlorohydrin, allyl bromide, methallyl bromide and crotyl bromide.

The following examples illustrate in detail certain of the compounds which comprise this invention and methods for their production. However, this invention is not to be construed as limited thereby in spirit or in scope. In these examples temperatures are given indegrees centigrade C.), relative amounts of materials in parts by weight, and pressures during vacuum distillations in millimeters (mm) of mercury.

Example 1 A mixture of 480 parts of 4-phenyl-4-tetrahydropyrancarboxylic acid and 122 parts of thionyl chloride is heated at reflux temperature for 2 hours after which the excess of thionyl chloride is removed by vacuum distillation. The residue is dissolved in benzene, solvent stripped under vacuum and distilled at about 128-131 C. and 2 mm. pressure. 365 parts of the 4-phenyl-4-tetrahydropyrancarbonyl chloride thus obtained are mixed with a solution of 235 parts of 8-hydroxyethyldiisopropylamine in 1300 parts of benzene and heated at reflux temperature for 10 hours. The precipitate is collected on a filter and dried in vacuo over sodium hydroxide. It is then dissolved in water and the aqueous solution is washed with ether, rendered alkaline and extracted with ether. This extract is washed with water, dried and the solvent is stripped. The B-diisopropylaminoethyl ester of 4- phenyl-4-tetrahydropyrancarboxylic acid is distilled at about -180 C. and 1.3 mmjpressure. It has the structural formula Example 2 140 parts of the above basic ester are dissolved in 2150 parts of anhydrous ether and treated with one equivalent of a 25% solution of hydrogen chloride in absolute Z-propanol. On standing at room temperature a white crystalline hydrochloride forms which, recrystallized from a mixture of ethyl acetate and Z-propanol, melts at about 147-148 C.

Example 3 A mixture of 449 parts of 4-phenyl-4-tetrahydropyrancarbonyl chloride and 246 parts of 6-diisopropylaminobutanol in 200 parts of xylene is heated at reflux temperature for 12 hours. The crude hydrochloride is collected on a filter, dried in vacuo and dissolved in water. The aqueous solution is washed with ether, rendered-alkaline and extracted with ether. This extract is washed with water, dried, solvent stripped and distilled at about -187" C. and 1.1 mm. pressure. It has the structural formula I i I? Example 5 A mixture of 460 parts of 4-phenyl-4-tetrahydropyrancarbonyl chloride, 334 parts of l-diisopropylamino-Z- propanol, and 2640 parts of benzene is refluxed for two hours. After. cooling, the crystalline precipitate is collected by filtration. The filtrate is diluted with ether and extracted with water containing a small amount of hydrochloric acid. The aqueous extracts are combined, made allcaline and extracted thoroughly with ether. The ethereal extracts are combined, washed with water, dried over anhydrous sodium sulfate, and the solvent distilled. The oily residue is dissolved in 250 parts of anhydrous ether and to this solution is added a slight excess of a 25% solution of hydrogen chloride in 2-propanol. The resulting o'il quickly granulates and the White crystalline product is then collected. After crystallizing from a mixture of 2-propanol and absolute ethyl acetate, the hydrochloride of the diisopropylamino-Z-propyl ester of 4-phenyl-4-tetrahydropyrancarboxylic acid melts at about 167-'l70 C. It has the structural formula om omonm m ooo OHOHio l omonm Ha? (1H2 n01 1120 OH:

Example 6 A mixture of 206 parts of 4-phenyl-4-tetrahydropyrancarboxylic acid, 54 parts of sodium methoxi-de, 200 parts of S-chloroethyl-di-n-propylamine hydrochloride and 4000 parts of 2-propanol is refluxed for 5 hours and then permitted to stand at room temperature. A crystalline precipitate forms which is collected on a filter and taken up in Water. The aqueous solution is rendered alkaline by addition of dilute sodium hydroxide and extracted with ether. This extract is washed with water, dried over anhydrous sodium sulfate, filtered and acidified with a slight excess of a 25% solution of hydrogen chloride in anhydrous Z-propanol. The hydrochloride of the fi di-npropylaminoethyl ester of 4-phenyl-4-tetrahydropyrancarboxylic acid thus obtained is recrystallized from methanol and ether. It melts at about 1823-184 C.

Example 7 Washed repeatedly with water, dried over anhydrous sodium sulfate and freed from solvent and unreacted di-(secondary butyl)aminoethano1 by vacuum distillation. The residual oil is dissolved in ether and treated with a slight excess of hydrogen chloride in Z-propanol. A solid hydrochloride is obtained which, recrystallized from ethyl acetate, melts at about 137-140 C. The salt of the fl-di(secondary butyl) aminoethyl ester of 4-phenyl- .4-tetrahydropyrancarboxylic acid thus obtained has the structural formula (OHz)-O:Hs Oi s /OOO-OH:OH: E

o omens-c2115 on: (DB1 1'101 Us: /OHa Example 8 A mixture of 143 parts of l-(fl-hydroxyethyl)-2,5- dimethylpyrrolidine, 225 parts of 4-phenyl-4-tetrahydropyrancarbonyl chloride and 800 parts of anhydrous benzene is heated at reflux for 45 minutes after which most of the solvent is removed under vacuum. The solid residue is taken up in methanol. The methanol solution is filtered and diluted with ether. The solid precipitate is collected on a filter and dried over anhydrous sodium hydroxide under vacuum. It is dissolved in water and the aqueous solution is Washed with ether, rendered alkaline and extracted with ether. This extract is washed with water, dried and evaporated to yield the 2,5 -dimethylpyrrolidinoethyl ester of 4phenyl-4-tetrahydropyrancarboxylic acid as an orange oil. The compound has the structural formula Example 9 Upon mixing of 157 parts of 1-(B-hydroxyethyl)-2,6- lupetidine and 225 parts of 4-phenyl-4 tetrahydropyrancarbonyl chloride in 800 parts of dry benzene, crystal lization occurs immediately. The reaction mixture is refluxed for 30 minutes and then submitted to vacutun distillation to remove most of the benzene. The solid residue i dissolved in methanol and the methanolic solution is filtered and diluted with ether. The crystals thus obtained are dissolved in water and the aqueous solution is rendered alkaline by addition of dilute sodium hydroxide and extracted with ether. This extract is Washed with Water and dried over anhydrous sodium sulfate. The solvent is stripped and the residue is dissolved in dry ether and treated with an excess of hydrogen chloride in 2-propanol. The solid precipitate is recrystallized from methanol and ether. The hydrochloride of the [ER-(2,6- lupetidino)ethyl ester of 4-phenyl-4-tetrahydropyrancarboxylic acid thus obtained melts at about -179 C.

It has the structural formula 1. A compound of the structural formula wherein Alk is a lower al'kylene radical separating the oxygen and nitrogen atoms attached thereto by at least two carbon atoms and NRR' is a member of the class consisting of di-n propylamino, diisopropylamino, d-i- (seconda-ry butyDamino, 2,5-dimethylpyrro1idino and 5 2,6-lupetidino radicals.

2. The ,B-diisopropyl aminoethyl ester of 4-pheny1-4- tetrahydropyrancarboxylic acid. tetrahydropyrancarboxyiic acid.

-3. The B-di-n-propylaminoethyi ester of 4-pheny1-4- tetrahydropyrancarb oxylic acid.

4. The fi-di(sec0ndary butyl)a.minoethy1 ester of 4- phenyl-4-tetrahydropyrancanboxylic acid.

6 5. The fl-(2,6-1upetidino)ethy1 ester of 4-phenyl-4- tetrahydropyrancarboxylic acid.

6. The 2,5-dimethylpyrro1idinoethyl ester of 4-phenyl- 4-tetrahydropyranca1 boxy1ic acid.

E-isleb: Berichte, vol. 74B, pp. 1433-51 (1941). Lefller et aL: JACS, vol. 55, pp. 365-70 (1932). 

1. A COMPOUND OF THE STRUCTURAL FORMULA 